WO2004108725A1 - Preparation of substituted quinoxalines from the dianline with 2,3-dihydroxy-1,4-dioxane - Google Patents

Preparation of substituted quinoxalines from the dianline with 2,3-dihydroxy-1,4-dioxane Download PDF

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Publication number
WO2004108725A1
WO2004108725A1 PCT/IB2004/001787 IB2004001787W WO2004108725A1 WO 2004108725 A1 WO2004108725 A1 WO 2004108725A1 IB 2004001787 W IB2004001787 W IB 2004001787W WO 2004108725 A1 WO2004108725 A1 WO 2004108725A1
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formula
dioxane
compounds
compound
process according
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PCT/IB2004/001787
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French (fr)
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Joseph Philip Rainville
Geraldine Patricia Taber
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Pfizer Products Inc.
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Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to DK04734570T priority Critical patent/DK1638971T3/en
Priority to EP04734570A priority patent/EP1638971B1/en
Priority to DE602004015986T priority patent/DE602004015986D1/en
Priority to BRPI0410613-0A priority patent/BRPI0410613A/en
Priority to JP2006508421A priority patent/JP2006526607A/en
Priority to MXPA05013084A priority patent/MXPA05013084A/en
Priority to PL04734570T priority patent/PL1638971T3/en
Priority to SI200430846T priority patent/SI1638971T1/en
Priority to CA002527337A priority patent/CA2527337A1/en
Publication of WO2004108725A1 publication Critical patent/WO2004108725A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention comprises a new process for the preparation of substituted quinoxalines by cyclization of the corresponding dianiline.
  • the present invention relates to a new process for the preparation of aryl fused azapolycyclic compounds having the formula
  • the present invention comprises a process for preparing a chemical moiety having the formula
  • the cyclization is preferably carried out at a temperature range of from about 20°C to about 25°C for a period of about 1 to about 25 hours and more preferably for about 1 to about 4- hours.
  • Suitable inert solvents are selected from the group consisting of aqueous alcohol, dioxane, tetrahydrofuran, DMF, DMSO, toluene and ethyl acetate.
  • the solvent is aqueous isopropanol.
  • the nitrogen protecting group Q is preferably a trifluoroacetyl group or a f-butoxy carbonyl group. More preferably Q is a trifluoroacetyl group.
  • Compounds of formula IV can be prepared by the synthetic method which is described and referred to in United States Patent No. 6,410,550.
  • inert solvent refers to a solvent system in which the components do not interact with starting materials, reagents, or intermediates of products in a manner that adversely affects the yield of the desired product.
  • the present invention provides a new process for the preparation of substituted quinoxalines (I) by cyclizing the corresponding dianiline (II) with 2,3-dihydroxy-1 ,4-dioxane.
  • the synthesis of compounds of formula II is disclosed in United States Patent No 6,410,550.
  • the present invention provides an alternative route to benzazepines of formula III in high purity and yield.
  • Prior attempts, as disclosed in United States Patent No. 6,410,550, to convert compounds of formula IV into compounds of formula III utilized either 40% aqueous glyoxal or the addition adduct of sodium bisulfite and ethane dione. Both of these reactions required purification steps.
  • the cyclization agent employed in the present invention should provide ease of handling, better stoichiometric accuracy, control of self-polymerization and reactivity at ambient temperatures.
  • Compounds of formula III are precursors to the aryl fused azapolycyclic compound of formula V and its pharmaceutically acceptable acid salts as illustrated below.
  • the acid salt is the L-tartaric acid salt.
  • the compound of formula V is useful in the treatment of central nervous system disorders as described above.
  • Removal of the nitrogen protecting group Q is carried out with methods well known in the art, such as, by heating in aqueous methanol in the presence of sodium carbonate.
  • Compounds of formula V bind to neuronal nicotinic acetylcholine specific receptor sites and are useful in modulating cholinergic function. Such compounds are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g..).
  • inflammatory bowel disease including but not limited to ulcerative colitis, pyoderma gangrenosum and Cr
  • the compounds of the formula V and their pharmaceutically acceptable salts can be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes.
  • Transdermal and oral administration are preferred.
  • These compounds are, most desirably, administered in dosages ranging from about 0.01 mg up to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed.
  • Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets may contain a variety of excipients, disintegrants, lubricating agents, and fillers.
  • Aqueous suspensions for oral administration may be combined with flavor, coloring matter, and diluents.
  • a solution of the active compound may be suitably buffered and may be diluted with a vegetable oil or propylene glycol.

Abstract

The present invention relates to a new process for the preparation of substituted quinoxalines (I) by cyclization of the corresponding dianiline with 2,3 dihydroxy-1,4-dioxane. In a preferred embodiment, the invention provides a process for the preparation of compounds having the formula III wherein Q is a nitrogen protecting group. Compounds of formula III and their derivatives are precursors to certain aryl fused azapolycyclic compounds which exhibit activity as agents for the treatment of neurological and psychological disorders.

Description

PREPARATION OP SUBSTITUTED QUIOXALINES FROM THE DIANLINE WITH 2 , 3-DIHYDROXY-l, 4- DIOXANE
Background of the Invention
The present invention comprises a new process for the preparation of substituted quinoxalines by cyclization of the corresponding dianiline.
More particularly, the present invention relates to a new process for the preparation of aryl fused azapolycyclic compounds having the formula
Figure imgf000002_0001
wherein Q is a nitrogen protecting group.
The synthesis, composition, and methods of use of certain aryl fused azapolycyclic 10 compounds of formula III are disclosed in United States Patent No. 6,410,550 which is incorporated herein by reference therein in its entirety.
The foregoing patent discloses the formation of compounds of formula III through the cyclization of the corresponding dianiline with aqueous glyoxal. Improvements in purity were needed in order to provide a more cost effective process. 15 Summary of the Invention
The present invention comprises a process for preparing a chemical moiety having the formula
Figure imgf000002_0002
comprising the step of cyclizing a chemical moiety of formula
Figure imgf000002_0003
with 2,3-dihydroxy -1 ,4- dioxane in an inert solvent as follows:
2,3-dihvdroxy-
1 ,4-dioxane
Figure imgf000003_0001
Figure imgf000003_0002
In a preferred embodiment the chemical moiety of formula I is a compound having the formula
Figure imgf000003_0003
and the chemical moiety of formula II is a compound of the formula
Figure imgf000003_0004
wherein Q is a nitrogen protecting group.
The cyclization of compound IV into compound III is illustrated below
2,3-dihydroxy- 1 ,4-dioxane
Figure imgf000004_0001
Figure imgf000004_0002
IV III
The cyclization is preferably carried out at a temperature range of from about 20°C to about 25°C for a period of about 1 to about 25 hours and more preferably for about 1 to about 4- hours. Suitable inert solvents are selected from the group consisting of aqueous alcohol, dioxane, tetrahydrofuran, DMF, DMSO, toluene and ethyl acetate. Preferably the solvent is aqueous isopropanol.
The nitrogen protecting group Q is preferably a trifluoroacetyl group or a f-butoxy carbonyl group. More preferably Q is a trifluoroacetyl group. Compounds of formula IV can be prepared by the synthetic method which is described and referred to in United States Patent No. 6,410,550.
As used herein, the expression "inert solvent" refers to a solvent system in which the components do not interact with starting materials, reagents, or intermediates of products in a manner that adversely affects the yield of the desired product. Detailed Description of the Invention
The present invention provides a new process for the preparation of substituted quinoxalines (I) by cyclizing the corresponding dianiline (II) with 2,3-dihydroxy-1 ,4-dioxane. The synthesis of compounds of formula II is disclosed in United States Patent No 6,410,550. In particular, the present invention provides an alternative route to benzazepines of formula III in high purity and yield. Prior attempts, as disclosed in United States Patent No. 6,410,550, to convert compounds of formula IV into compounds of formula III utilized either 40% aqueous glyoxal or the addition adduct of sodium bisulfite and ethane dione. Both of these reactions required purification steps.
The cyclization agent employed in the present invention should provide ease of handling, better stoichiometric accuracy, control of self-polymerization and reactivity at ambient temperatures. Compounds of formula III are precursors to the aryl fused azapolycyclic compound of formula V and its pharmaceutically acceptable acid salts as illustrated below. Preferably the acid salt is the L-tartaric acid salt. The compound of formula V is useful in the treatment of central nervous system disorders as described above.
Removal of the nitrogen protecting group Q is carried out with methods well known in the art, such as, by heating in aqueous methanol in the presence of sodium carbonate.
Figure imgf000005_0001
III v wherein Q is as defined above.
Examples of specific compounds of the formula V are the following compounds:
4-ethynyl-5-chloro-10-aza-tricyclo[6.3.02'7]dodeca-2(7),3,5-triene;
3-trifluoromethyl-10-aza-tricyclo[6.3.02,7]dodeca-2(7),3,5-triene;
4,5-bistrifluoromethyi-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-choro-5-trifluoromethyl-10-aza-tricycIo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-nitro-10-aza-tricyclo[6.3.02,7]dodeca-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.02,7]dodeca-2(7),3,5-triene
4-fluoro-10-aza-tricyclo[6.3.02,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.02,7]dodeca-2(7),3,5-triene;
4,5-difluoro-10-aza-tricyclo[6.3.02,7]dodeca-2(7),3,5-triene; and pharmaceutically acceptable salts thereof.
Compounds of formula V bind to neuronal nicotinic acetylcholine specific receptor sites and are useful in modulating cholinergic function. Such compounds are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g.. dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome.
The compounds of the formula V and their pharmaceutically acceptable salts (hereafter "the active compounds") can be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These compounds are, most desirably, administered in dosages ranging from about 0.01 mg up to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets may contain a variety of excipients, disintegrants, lubricating agents, and fillers. Aqueous suspensions for oral administration may be combined with flavor, coloring matter, and diluents. For parental administration, a solution of the active compound may be suitably buffered and may be diluted with a vegetable oil or propylene glycol.
The following examples are provided for the purpose of further illustration and are not intended to limit the scope of the claimed invention. EXAMPLES 1
Cyclization of 2,3,4,5-tetrahvdro-3-(trifluoroacetyl)-1 ,5-methano-1 H-3-benzazepine- 7.8-diamine (compound IV) with 2, 3-dihyroxy-1 ,4-dioxane to form 7,8,9,10-tetrahvdro-8- (trifluoroacetyl)-6,10-methano-6H-pyrazinof2,3-hir3lbenzazepine (compound III).
To a 200ml aqueous isopropanolic solution (80:20 IPO:H20) of compound II (8.2g, 28.9mmol), an equimolar quantity of 2,3-dihydroxy-1 ,4-dioxane is added and the mixture stirred at 20-25°C for 15 hours. The solution is concentrated by distillation to 5mL/g of compound II, and cooled. Water is added and the product is granulated at ambient temperature then isolated by vacuum filtration. Yield: 7.9g in 89%. Purity: High Performance Liquid Chromatography (HPLC) 99.2 weight % versus external standard
Melting Point: 171.5°C
EXAMPLE II Deprotection of 7,8.9,10-tetrahydro-8-(trifluoroacetyl)-6.10-methano-6H-pyrazinor2.3- hir31benzazepine (compound IV) to form 7,8,9.10-tetrahydro-6.10-methano-6H-pyrazinor2.3- hlPlbenzazepine (compound V) 13.4g, 335mmol of sodium hydroxide pellets are dissolved in 335mL of process water. To this, 33.21 g, 108mmo! of compound I and 83ml of methylene chloride (2.5mL/g of compound I) are added and reacted at 20-25°C for 3 to 4 hours. Upon reaction completion, 250mL of methylene chloride (7.5mL/g of compound I) are added and the mixture is stirred, settled and separated. The product rich methylene chloride is displaced with methanol and treated with 25 w/w % Darco Kbb carbon. The carbon is filtered away and the methanolic free base solution of compound III is treated with a methanolic solution of L-tartaric acid 1.1 molar equivalents. The product slurry is granulated at ambient temperature and filtered to give the L-tartaric acid salt of compound III (7,8,9, 10-tetrahydro-6,10-methano-6H- pyrazino[2,3-h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1 :1)) Yield: 31.2g in 80% Purity: HPLC >99.0 weight % versus external standard

Claims

We Claim
1. A process for preparing a chemical moiety of formula I
Figure imgf000008_0001
comprising the step of cyclizing a chemical moiety of formula II
Figure imgf000008_0002
with 2,3-dihydroxy -1 ,4- dioxane in an inert solvent.
2. A process according to claim 1 wherein said chemical moiety of formula I is a compound having the formula
Figure imgf000008_0003
and said chemical moiety of formula II is a compound of formula
Figure imgf000008_0004
wherein Q is a nitrogen protecting group.
3. A process according to claim 1 wherein said cyclization is conducted at a temperature range of from about 20°C to about 25°C for a period of from about 1 to about 25 hours.
4. A process according to claim 1 wherein said inert solvent is selected from the group consisting of aqueous alcohol, dioxane, tetrahydrofuran, DMF, DMSO, toluene, and ethyl acetate.
5. A process according to claim 4 wherein said inert solvent is aqueous isopropanol.
6. A process according to claim 2 wherein the nitrogen protecting group Q is a trifluoroacetyl group or a f-butoxycarbonyl group.
7. A process according to claim 6 wherein the nitrogen protecting group is a trifluoroacetyl group.
8. A process according to claim 3 wherein said cyclization is conducted for a period of from about 1 to about 4 hours.
PCT/IB2004/001787 2003-06-04 2004-05-24 Preparation of substituted quinoxalines from the dianline with 2,3-dihydroxy-1,4-dioxane WO2004108725A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DK04734570T DK1638971T3 (en) 2003-06-04 2004-05-24 Preparation of Substituted Quinoxalins from the Dianiline with 2,3-Dihydroxy-1,4-Dioxane
EP04734570A EP1638971B1 (en) 2003-06-04 2004-05-24 Preparation of substituted quinoxalines from the dianiline with 2,3-dihydroxy-1,4-dioxane
DE602004015986T DE602004015986D1 (en) 2003-06-04 2004-05-24 PREPARATION OF SUBSTITUTED CHINOXALINES FROM DIANILINES WITH 2,3-DIHYDROXY-1,4-DIOXANE
BRPI0410613-0A BRPI0410613A (en) 2003-06-04 2004-05-24 preparation of substituted quinoxaline from dianlin with 2,3-dihydroxy-1,4-dioxane
JP2006508421A JP2006526607A (en) 2003-06-04 2004-05-24 Method for producing substituted quinoxaline from dianiline using 2,3-dihydroxy-1,4-dioxan
MXPA05013084A MXPA05013084A (en) 2003-06-04 2004-05-24 Preparation of substituted quinoxalines from the dianline with 2,3-dihydroxy-1,4-dioxane.
PL04734570T PL1638971T3 (en) 2003-06-04 2004-05-24 Preparation of substituted quinoxalines from the dianiline with 2,3-dihydroxy-1,4-dioxane
SI200430846T SI1638971T1 (en) 2003-06-04 2004-05-24 Preparation of substituted quinoxalines from the dianiline with 2,3-dihydroxy-1,4-dioxane
CA002527337A CA2527337A1 (en) 2003-06-04 2004-05-24 Preparation of substituted quinoxalines from the dianline with 2,3-dihydroxy-1,4-dioxane

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US47558903P 2003-06-04 2003-06-04
US60/475,589 2003-06-04

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CA (1) CA2527337A1 (en)
CL (1) CL2004001271A1 (en)
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Cited By (7)

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WO2006090236A1 (en) * 2005-02-24 2006-08-31 Pfizer Products Inc. Preparation of high purity substituted quinoxaline
WO2009155403A2 (en) * 2008-06-19 2009-12-23 Teva Pharmaceutical Industries Ltd. Processes for the preparation of varenicline and intermediates thereof
WO2010023561A1 (en) * 2008-09-01 2010-03-04 Actavis Group Ptc Ehf Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof
WO2011110954A1 (en) 2010-03-09 2011-09-15 Actavis Group Ptc Ehf Highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity
US8039620B2 (en) 2008-05-22 2011-10-18 Teva Pharmaceutical Industries Ltd. Varenicline tosylate, an intermediate in the preparation process of varenicline L-tartrate
WO2011154586A2 (en) 2010-06-11 2011-12-15 Medichem, S. A. Improved methods for the preparation of quinoxaline derivatives
US8178537B2 (en) 2009-06-22 2012-05-15 Teva Pharmaceutical Industries Ltd. Solid state forms of varenicline salts and processes for preparation thereof

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006090236A1 (en) * 2005-02-24 2006-08-31 Pfizer Products Inc. Preparation of high purity substituted quinoxaline
US8039620B2 (en) 2008-05-22 2011-10-18 Teva Pharmaceutical Industries Ltd. Varenicline tosylate, an intermediate in the preparation process of varenicline L-tartrate
WO2009155403A2 (en) * 2008-06-19 2009-12-23 Teva Pharmaceutical Industries Ltd. Processes for the preparation of varenicline and intermediates thereof
WO2009155403A3 (en) * 2008-06-19 2010-11-11 Teva Pharmaceutical Industries Ltd. Processes for the preparation of varenicline and intermediates thereof
WO2010023561A1 (en) * 2008-09-01 2010-03-04 Actavis Group Ptc Ehf Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof
US8314235B2 (en) 2008-09-01 2012-11-20 Actavis Group Ptc Ehf Process for preparing varenicline, varenicline intermediates, pharmaceutically acceptable salts thereof
US8178537B2 (en) 2009-06-22 2012-05-15 Teva Pharmaceutical Industries Ltd. Solid state forms of varenicline salts and processes for preparation thereof
WO2011110954A1 (en) 2010-03-09 2011-09-15 Actavis Group Ptc Ehf Highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity
WO2011154586A2 (en) 2010-06-11 2011-12-15 Medichem, S. A. Improved methods for the preparation of quinoxaline derivatives
WO2011154586A3 (en) * 2010-06-11 2012-03-22 Medichem, S. A. Improved methods for the preparation of quinoxaline derivatives

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CA2527337A1 (en) 2004-12-16
BRPI0410613A (en) 2006-06-20
DK1638971T3 (en) 2008-10-27
EP1638971B1 (en) 2008-08-20
SI1638971T1 (en) 2008-12-31
CL2004001271A1 (en) 2005-04-22
PL378491A1 (en) 2006-05-02
ATE405566T1 (en) 2008-09-15
TWI251594B (en) 2006-03-21
TW200500365A (en) 2005-01-01
US20070185327A1 (en) 2007-08-09
PT1638971E (en) 2008-10-23
PL1638971T3 (en) 2009-01-30
ES2310730T3 (en) 2009-01-16
EP1638971A1 (en) 2006-03-29
DE602004015986D1 (en) 2008-10-02

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